Abstract 5301: Flecainide Blocks Cardiac Ryanodine Channels and Prevents Catecholaminergic Ventricular Tachycardia in Cardiac Calsequestrin Null Mice
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic syndrome due to cardiac Ca2+ release channel (RYR2) or cardiac calsequestrin (CASQ2) mutations. VT is caused by spontaneous Ca2+-release from the sarcoplasmic reticulum (SR) that generates after-depolarizations and triggered beats during catecholamine surge. Current CPVT treatments (β-blockers, Ca2+ channel blockers) are incompletely effective. In preliminary studies, we recently found that flecainide, a class 1c Na+ channel blocker, suppressed ventricular arrhythmia in Casq2 null (Casq−/−) mice, a model of CPVT. We investigated the effect of flecainide on the incidence of exercise-induced CPVT in Casq2−/− mice, on cardiac Ca2+ handling in Casq2−/− myocytes loaded with Fura-2 AM, and on RyR2 channels reconstituted in lipid bilayers. In vivo, flecainide (20 μg/g intraperitoneally) completely prevented exercise-induced CPVT (n=11, p<0.05) and dramatically reduced exercise-induced ventricular ectopy (PVCs/min: vehicle: 214.7±59.9 vs. flecainide: 0.1±0.2, n=11 mice, p=0.003). In isoproterenol-stimulated Casq2−/− myocytes, flecainide (6 μmol/l) reduced triggered beats by over 70% (p<0.001). Unexpected for a Na+ channel blocker, flecainide also reduced SR Ca2+ leak (Ca2+ fluorescence ratio: vehicle: 0.12±0.01 vs. flecainide: 0.08±0.01, n=54 per group, p=0.02) and suppressed the rate of spontaneous Ca2+ releases (SCRs) from the SR (SCRs/min: vehicle: 48±5 vs. flecainide: 29±5, n=45 per group, p=0.006), suggesting flecainide directly inhibits SR Ca2+ release. Lipid bilayer experiments confirmed a direct action of flecainide on RyR2 SR Ca2+ release channels: Flecainide (5 μmol/l) significantly reduced the open probability of RyR2 channels reconstituted in lipid bilayers (n=3, p<0.05), with an IC50 of approximately 20 μmol/l. We report a heretofore unrecognized inhibitory action of flecainide on RyR2 channels, which together with flecainide’s inhibition of Na+ channels may explain the complete suppression of CPVT in Casq2−/− mice. Flecainide should be considered for a clinical trial in CPVT patients.
This research has received full or partial funding support from the American Heart Association, AHA National Center.